By Ana Espino | Published on June 15, 2026 | 4 min read
Since its discovery in 1976, the Ebola virus has remained
one of the most feared infectious agents in the world. Responsible for Ebola
virus disease (EVD), it causes a severe hemorrhagic fever that can progress to
multiple organ failure and death. Despite recent advances in the development of
vaccines and treatments, many questions remain regarding the precise mechanisms
of infection and the evaluation of medical countermeasures.
Most current knowledge is based on animal studies.
Historically, researchers infected animals through so-called “artificial”
routes, particularly intramuscular or intraperitoneal injection, in order to
precisely control the administered dose. In humans, however, infection
generally occurs through contact between mucous membranes or broken skin and
infected biological fluids. These differences raise an important question: does
the route of infection influence disease progression? To address this, American
researchers reviewed the main animal models used in Ebola virus research and
compared the consequences of different routes of infection.
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When the Route of Exposure Changes Disease Progression
The authors analyzed data obtained in several animal
species, including nonhuman primates, mice, hamsters, guinea pigs, and ferrets.
They compared infections induced through artificial routes, such as
intramuscular or intraperitoneal injection, with those produced through routes
that more closely resemble natural transmission, including nasal, oral, ocular,
and aerosol exposure.
The findings show that the route of infection strongly
influences disease progression. In models using intramuscular injection,
clinical signs appear rapidly and the disease course is generally more abrupt.
By contrast, mucosal exposure often leads to a slower progression, with a
longer delay before symptom onset and death. This prolonged course more closely
resembles what is observed in human patients.
Researchers also identified differences in the organs
affected. Mucosal infections are more commonly associated with pulmonary and
gastrointestinal lesions, whereas some artificial routes cause more pronounced
liver involvement. In nonhuman primates, guinea pigs, and ferrets, intranasal
exposure is notably associated with significant lung involvement and earlier
viral shedding, potentially facilitating virus transmission.
The review also confirms that nonhuman primates remain the
reference model for accurately reproducing human disease. However, ferrets
appear to be a particularly promising alternative, as they develop severe
disease after infection with wild-type Ebola virus without requiring prior
viral adaptation.
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Toward Models That Better Reflect Human Reality?
This review highlights that the route of exposure is a key
determinant in the study of Ebola virus disease. Models based on mucosal
infection appear to reproduce more faithfully the timing, clinical
manifestations, and transmission mechanisms observed in humans.
However, the authors note that these models also have
limitations. Natural-route infections often result in more variable mortality
and are more dependent on the viral dose administered, which can complicate the
evaluation of new treatments or vaccines. Conversely, artificial routes produce
more consistent outcomes and facilitate preclinical studies.
Despite these constraints, the increasing use of models that
reproduce natural transmission routes could improve understanding of disease
mechanisms and help investigate phenomena that remain poorly understood, such
as long-term sequelae and viral persistence in survivors. This represents an
important step toward improving future strategies for the prevention and
management of Ebola virus disease.
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions. 
